Nov., 1949
3613
RZ-SUBSTITUTED XAPHTHOQUINONE ANTIMALARIALS [CONTRIBUTION FROM THE CHEMICAL
LABORATORY OF HARVARD UNIVERSITV]
Naphthoquinone Antimalarials. XXIII. Bz-Substituted Derivatives1 BY LOUISF. FIESER AND RUSSELL H. BROWN^ In the few instances previously investigated the Related compounds carrying a chlorine atom a t substitution of alkyl or hydroxyl groups in the the 6 - or 7-position were prepared starting with 6benzenoid ring of a 2-hydroxy-3-alkyl-l,4-naph-chloro-1,4-naphthoquinone (IX), available from thoquinone has been found to practically obliter- chloroprene and benzoquinone. The Thiele reacate antimalarial a ~ t i v i t y . Since ~ the case of ata- tion afforded a separable mixture of the two hy0
SO&H, I
T
I1
IV
I11
0 I1
0 II
0 I1
0
0
0
VI
brine would suggest the possibility of a more favorable result from the introduction of @-methoxyor P-chloro substituents into the aromatic ring, severa1 new compounds of this type have been examined. Two series of P-bz-methoxyquinones were prepared starting with 7-methoxy1-nitroso-2-naphthol (11), available from naphthalene-2,7-disulfonicacid in three known steps. By procedures worked out IX for 1-nitroso-2-naphthol, I1 was converted through the aminonaphtholsulfonic acid 111, the quinone sulfonate IV, and the dimethoxy quinone V into 2-hydroxy-7methoxy-l,4-naphthoquinone(VI). By the peroxide alkylation reaction this was converted into 3-alkyl derivatives having from seven to eleven carbon atoms in the side-chain. These were converted by the modified Hooker oxidation4 reaction into the next lower homologs in which, in consequence )f the opening and reclosing of the quinone ring, the methoxy group is transposed to the 6-position (VIII). None of the compounds tested showed m y antirespiratory a ~ t i v i t y ,whereas ~ the corresponding methoxyl-free compounds are all active, even though the methoxyl substitution produces little change in the extraction constantsU6 I
(1) This work was supported in part by grants from the Rockefeller Foundation and Research Corporation. (2) Abbott Laboratories postwar Fellow, 1945-1948. (3) Fieser and Richardson, THIS JOURNAL,TO, 3156 (1948): Fieser, Leffler and co-workers, ibid., TO, 3212 (1948). (4) Fieser and Fieser, ibid., 70, 3215 (1948). ( 5 ) Heymann and Fieser, J . Pharmacd. Ex#. Thcrafi., 94, 97 (1948); Fieser and Heymann, J . B i d . Chcm., 1'76, 1363 (1948). (6) Fieser, Ettlinger and Fawaz, THISJOURNAL, TO, 3228 (1948).
I1
0
\'I1
VI11
droquinone triacetates, each of which was converted into the corresponding hydroxychloronaphthoquinone. One of these was identified as 0
x
OAc XI 0
(+7-chloro isomer)
f XI1
SI11
the 2-hydroxy-6-chloro isomer by synthesis from the known 6-chloro-1-naphthol (XII) through the dinitro derivative X I I I ; this on reduction and OXidation afforded 6-chloro-2-amino-1,4-naphthoquinone-4-imine, which yielded X I on hydrolysis. The two hydroxychloroquinones were then alkylated with the peroxide from y-cyclohexylbutyric acid, but neither product showed appreciable antirespiratory activity* Experimental' 2-Hydroxy-3-alkyl-7(6) -methoxy-1,4-naphthoquinones 1-Nitroso-2-hydroxy-7-methoxynaphthalene .-Additional data on previously described procedures are as follows. Naphthalene (128 g.) was sulfonated with 9570 (7) The melting points are all corrected.
LOUISF. FIESER AND RUSSELL H. BROWN
3616
V O l. 71
TABLE I 1,4-1L'APHTHOQUINOSES NO
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Substituents
Fbp'*
Solvent
214-215 EtOH 2,7-(OC&)z 2-OH-7-OCH3 220-222 EtOH 2-OH-7-OCH3-3-(CH2)3-cyclohexyl 119-120 MeOH 2-OH-7-OCH3-3-CHz-cyclohexyl 164-165 Pet. ether 2-OH-7-OCH3-3-CllH23-n 94-95 MeOH 2-OH-7-OCH3-3-CgHie-n 97-98 MeOH 2-OH-6-OCH3-3-(CH2)z-cyclohexyl 137-138 MeOH 2-OH-6-OCHs-3-cyclohexyl 142-143 MeOH 2-OH-6-OCH3-3-ClnH21-n 110-111 MeOH 2-OH-6-Cl 210-212 MeOH 2-OH-6-C1-3-(CH2)8-cyclohexyl 164-165 MeOH 2-OH-7-Cl 205-207 MeOH 2-OH-7-C1-3-(CH2)3-cyclohexyl 132-133 MeOH ~-OH-~-(CHZ)~CH=CHZ 70-71 MeOH 2-OH-3-(CHz)sCH=CH? 62-63 MeOH 2-OH-3-(CHz)aCH=CHz 86-87 MeOH 2-OH-3-(CH2)aCH=CHz 78-79 MeOH 2-OH-3- (CH2)3CH=CHz 101-102 MeOH 2-OH-3-(CHz)zCH=CHz 98-100 MeOH
sulfuric acid (350 cc.) for four hours a t 160"81@and the cooled solution poured onto 500 g. of ice and 1.5 1. of water and neutralized with 450 g. of powdered calcium carbonat: or 300 g. of quicklime. The mixture was filtered a t 40 and the residual calcium sulfate extracted twice with 500cc. portions of boiling water. The combined filtrates were evaporated to dryness and the mixture of 2,6- an; 2,7-sulfonates was dried to constant weight a t 200 ; yield 263-285 g. Three parts of the crude calcium salt was treated with 5 parts of boiling water and the mixture was filtered by suction a t the boiling point and the solid washed with a little hot water. Evaporation of the filtrate and dehydration as above gave 190 g. (58%) of calcium 2,7-disulfonate. Conversion to 2,7-dihydroxynaphthalenes was effected by fusing 100 g. of calcium salt with 200 g. of crude potassiumohydroxide flakes and 50 cc. of water for four hours a t 250 . The granular mixture was added while hot in small portions with stirring to 800 cc. each of 3670 hydrochloric acid and water and the granular 2,7-dihydroxynaphthalene that separated after cooling a t 0" overnight was crystallized twice from water (100 cc.) ; yield 21.8-24.0 g. (44-49%), m. p. 189-190 . Z-Hydroxy-7-rnetho~ynaphthalene~~ was prepared as outlined by Fischer and Hammerschmidtll by slowly adding 5.6 g. of potassium hydroxide in 100 cc. of water to a stirred mixture of 16 g. of 2,7-dihydroxynaphthalene; 150 cc. of water, and 20 cc. of dimethyl sulfate a t 40". After fifteen minutes 10% alkali was added to the point of distinct alkalinity, the solution was filtered by suction into dilute hydrochloric acid containing sodium sulfite and the residual diether washed repeatedly with warm alkali. The monomethyl ether separated as large white leaflets and was crystallized from ligroin; yield 9.76 g. (56%), m. p. 116-117'. The 1-nitroso derivative" was prepared by slowly adding 20.3 g. of sodium nitrite in 150 cc. of water to a stirred solution a t 0 " of 51 g. of 2-hydroxy-7-methoxynaphthalene in 300 cc. of acetic acid containing 30 cc. of water. The resulting slurry was allowed to stand a t room temperature for several hours, diluted with water, and the solid collected, washed, dried, and crystallized from 400 (8) Weber, BEY.,14, 2206 (1881). (9) Haller and Lynch, I n d . Eng. Ckcm.,16, 274 (1924). (10) Buiigly and Decktr, B c r . , S8, 3272 (1905). (11) 0. Fischer and Hammerschmidt, J. p v o k l . C'hetn., 94, 25 (lY16).
Form
Orange needles Orange needles Yellow needles Fine needles Leaves Leaves Large leaves Fine blades Blades Micro cryst. Small leaves Micro cryst. Leaflets Leaflets Leaflets Leaflets Leaflets Leaflets Tiny plates
Formula
7 .4nalyses, Yo----. Carbon Hydrogen Calcd. Found Calcd. Found
CIZHIOO~ 66.05 CllH804 64.71 C Z O H Z ~ O73.12 ~ C I ~..H ~. O O72.00 ~ 73.70 42H3004 72.71 CzoHzeOc C I Q H ~ ~ O72.58 ~ 71.30 C17HlsO4 73.23 CZlHZsO4 CIOHSO~CI57.55 68.58 57.55 68.58 76.47 76.01 75.54 74.99 74.35 73.69 ~
66.32 64.93 73.41 72.36 73.86 72.97 72.67 71.57 73.15 57.53 68.72 57.57 68.39 76.60 75.95 75.35 75.00 74.52 73.77
4.62 3.95 7.37 6.71 8.44 7.93 7.06 6.33 8.19 2.42 6.36 2.42 6.36 7.43 7.09 6.71 6.29 5.82 5.30
4.95 4.09 7.48 7.03 8.28 8.07 6.79 6.21 8.32 2.49 6.:37 2.40 6.20 7.61 7.39 6.98 6.77 6.05 5.40
cc. of methanol. The yield of bright red needles, m. p. 121-125', was 41 g. (69%). 7-Methoxy-1,Z-naphthoquinonewas obtained from the nitroso derivative by reduction and oxidation; it formed crimson microprisms from ethanol, m. p. 143-145". Anal. Calcd. for C11H803: C, 70.20; H, 1.28. Found: C, 70.01; H , 4.18. 2,7-Dimethoxy-l,4-naphthoquinone(Table I) .-By reaction with sodium bisulfite and acidification by a procedure worked out for the methoxyl-free ~ornpound,'2~'~ 67 g. of l-nitroso-2-hydroxy-7-methoxynaphthalene yielded 74 g. (84%) of 1-amino-7-methoxy-2-naphthol-4sulfonic acid as a light gray granular solid. Oxidation of 83 g. of this material with nitric acid by the procedure of Fieser and Martin14 gave 73 g. (83%) of ammonium 7methoxy-1,2-naphthoquinone-4-sulfonate.Treatment of this substance with methanol and sulfuric acid according to Fieser and Martin afforded satisfactory 2,7-dimethoxy1,4-naphthoquinone in 72y0 yield (No. 1, Table I ) . The dimethoxy compound dissolved rapidly in hot dilute alkali, and acidification of the red solution gave 2-hydroxy7-methoxy-1,4-naphthoquinonein 82.5y0 yield ( N o . 2). Alkyl Derivatives.-The 2-hydroxy-7-methoxy-3-cyclohexylpropyl and 3-undecyl derivatives Nos. 3 and 5 were prepared by peroxide alkylation in the usual manner.16 A succession of Hooker oxidationsS then gave, alternately, members of the 6-methoxy and the 7-methoxy series; thus: 3 + 7 + 4 + 8, and 5 -+ 9 + 6. 2-Hydroxy-3-alkyl-6 (7)-chloro-l,4naphthoquinones 6-Chloro-1,4-naphthoquinone16was prepared by the procedure described by Fieser for the parent quinone.17 +Benzoquinone (108 g.) was condensed with chloroprenexs (89 9.) in acetic acid (500 cc.) a t room temperature (12) Fieser, Org. Syn., Coll. Vol. 11, 42 (1943). JOURNAL, 48, 2929 (1926); Martin and Fieser, (13) Fieser, THIS Org. Syn., 21, 91 (1941). (14) Fieser and Martin, Org. S y n . , 21, 66 (1941). (15) Fieser, Lemer and co-workers, THISJ O U K N A L , 70,3175 (1948). (16) Carothers and Collins, U. S. Patent 1,967,862 (1934) [C. A , , 28, 5994 (1934)l; Koslov and Talybov, J. Gcn. Chew?.( U . S. S. R 1, 9, 1827 (1939). (17) Fieser, THISJ O L - R X A L , 70, 3165 (1948). (18) Obtained by fractionation of a stabilized chloroprene-xylene sulutiou kiudly supplied by the clu Pant Company.
Nov., 1949
Rz-SUBSTITUTED NAPIITHOQUINONE ANTIMALARIALS
361i
dinitro phenol yielded 2.0 g. (59%) of 2-amino-7-chlorofor forty-eight hours. Isomerization with hydrochloric acid-stannous chloride resulted in crystallization of 149 g. 1,4-naphthoquinone-4-iminehydrochloride as deep red (76%) of light gray 6-chloro-5,8-dihydro-1,4-naphtho- crystals. A suspension of 1.5 g. of this salt in 50 cc. of quinone (recrystallized sample, m. p. 197-198'). Oxida- 5% aqueous potassium hydroxide solution was boiled for fifteen minutes and the resulting deep red solution was tion in acetic acid with nitrous acid and then dichromate mixture gave bright yellow 6-chloro-1,4-naphthoquinone, acidified. The amorphous precipitate of the hydroxym. p. 102-105", in 77% yield from the dihydronaphtho- quinone (0.72 g.) was purified in the form of the hydrohydroquinone. $rystallization from ether raised the quinone triacetate, which crystallized from 40 cc. of methanol in the form of colorless needles, m. p. 140-143 '. m. p. to 106-107 . 6 - and 7-Chloro-1,2,4-triacetoxynaphthalene.-A sus- After five recrystallizations the analytical sample melted pension of 58 g. of 6-chloro-1,4-naphthoquinonein 120 cc. a t 143-144" and gave no depression when mixed with the described above. of acetic anhydride was cooled to 0" and treated with 6 7-chloro-l,2,4-triacetoxynaphthalene cc. of boron fluoride etherate. After standing a t room Anal. Calcd. for C16H1306Cl: C, 57.08; H , 3.89. temperature for several hours, the mixture was warmed Found: C, 57.14; H, 3.73. briefly on the steam-bath and again let stand. The suspension of crystals in dark brown liquor was poured into Other Observations water and the product collected as a tan solid, m. p. 120The 2-hydroxy-3-&-alkenyl-l,4-naphthoquinones listed 135"; yield 65 g. (63%). Fractionation from methanol was tedious but afforded substantial amounp of the less as Nos. 14-19 in Table I were all prepared from 2-hydroxysoluble 7-chloro compound, m. p. 163-164 , and of the 3-AB-decenyl-1,4-naphthoquinone21 by the modified Hooker oxidation p r o c e d ~ r e . ~We attempted to determore soluble 6-chloro isomer, m. p. 143-144". the nature of the water-soluble products obtainablez2 Anal. Calcd. for C16H1306C1: c, 57.08; H, 3.89. mine by the action of acetyl sulfuric acid in acetic acid solution Found: (164') C, 57.34; H, 3.88; (144') C, 57.31; €1, on the homologs having 8, 7 and 6 methylene groups in 3.95. the side-chain. The results were not fully conclusive but 6 - and 7-Chloro-2-hydroxy-l,4-naphthoquinone(Table suggested that the products have the side-chain structure : I) was prepared by the hydrolysis procedure of Fieser.I7 -(CH2)nCHOHCH2S03H. Thus the product from S o . 7 Thus 8.4 g. of 7-chloro-1,2,4-triacetoxynaphthalenewas yielded an aniline salt, in. p. 152-154', and a p-toluidine added in ten minutes to a suspension of 7 g. of sodium salt, m. p. 163-165" (from alcohol-water) of the following methoxide in 70 cc. of methanol, stirred in an ice-bath. analyses. After one hour the red salt was collected (more from mother Anal. Aniline salt. Calcd. for C X H ~ ~ O ~ N C,S61.33; : liquor with air), dissolved in hot water, and the filtered H. 6.38. Found: C. 61.61: H. 6.38. b-Toluidine salt. solution acidified ; yield of bright yellow microcrystalline Calcd. for Cz~H3307Nk: C, 62.06; H, 6.kl. Found: C, product 4.5 g . (91%). The isomer was obtained in 81% 62.54; H , 6.67. yield. These substances were completely devoid of antiThe properties and analyses of the products of peroxide respiratory activity, as was a sulfonation product obtained alkylation are listed in Table I . in crude form from an oil resulting from alkylation of hydroxynaphthoquinone with the peroxide from oleic Synthesis of 2-Hydroxy-7-chloro-l,4-naphthoquinone acid. Oxidation of 3-Alkyl-1-tetralones with Selenium Di7-Chloro-I-naphthol.-In the preparation of this suboxide.-The method of Xi'eygand and SchrOderz3for the stance according to Erdmann and K i r ~ h h o f f the ' ~ reaction was mixture from 70 g. of p-chlorobenzaldehyde, 41 g. of fused synthesis of 2-hydroxy-3-alkyl-l,4-naphthoquinones sodium acetate and 50 g. of succinic anhydride was treated briefly investigated with the following results. 3-Ethylwith water and 10 g. of the unchanged aldehyde was re- 1-tetralone, b . p. 112-114' a t 2 mm., on reaction with moved by steam distillation. The residue was diluted with selenium dioxide in ethanol afforded 2-hydroxy-3-ethyl1,4-naphthoquinone, m. p. 137-138", in 3570 yield; the water to about 2 liters, filtered, and acidified with hydrosubstance was compared with an authentic sample from chloric acid. The crude precipitated p-chlorophenylthe Hooker collection.2* paraconic acid [containing p-chlorobenzoic acid and p-(p2-Hydroxy-3-methyl-l,4-phenanthrenequinone was obchlorobenzal) -propionic acid] weighing 40 g. was heated in a distilling flask until the evolution of carbon dioxide tained by the same method in comparable yield; it fzrmed bright orange needles from benzene, m. p. 215-217 . had subsided and distilled ; the yellow, solidified distillate was dissolved in dilute alkali. The solution was extracted Anal. Calcd. for CljHIOOa:C, 75.61; H , 4.23. Found: with ether to remove oily material and neutralized with C, 75.44; H, 4.25. carbon dioxide, when the 7-chloro-1-naphthol separated Summary as almost colorless, fine needles, rn. p. 125-130"; yield 8 g. (22%). 02e crystallization from water raised the Substances related to actively antimalarial 2m. p. t o 130-131 2,4-Dinitro-7-chloro-l-naphtholwas prepared by the hydroxy-3-alkyl-1,4-naphthoquinones but having exact procedure described for the chlorine-free substance20 methoxyl or chloro substituents in the @-positions and obtained as the ammonium salt in 67y0 yield. The free phenol after several crystallizations from alcohol of the benzenoid ring were synthesized and found to be devoid of activity. melted a t 169-170", dec. Anal. Calcd. for CloHaOjNzCl: C, 44.71; H, 1.88. CONVERSE MEMORIAL LABORATORY Found: C, 44.70; H , 1.75. CAMBRIDGE 38, MASSACHUSETTS RECEIVED MAY12, 1949 2-Hydroxy-7-chloro-l,4-naphthoquinone.-By the pro(21) Fieser, Leffler and co-workers, THIS J O U R N A L , TO, 3195 cedure indicated,2o 4 g. of the ammonium salt of the
.
(19) Erdmann and Kirchhoff, A n n . , 247, 366 (1888). (20) Fieser, "Experiments in Organic Chemistry," 2nd ed., D. C. Heath Co., Boston, Mass., 1941.
(1948). (22) Fieser, ibid., 70, 3232 (1948). (23) Weygand and Schrdder, Ber., 74, 1844 (1941). (24) Hooker, THISJOURNAL, 58, 1174 (1936).
